In vitro studies have shown that Candida albicans yeast cells and hyphae are activators of the human complement system. The importance of the complement system in host resistance to candidiasis has been demonstrated by complement depletion studies which found that experimental animals with a deficient complement system have a markedly decreased resistance to candidiasis. Numerous mammalian cells have receptors for C3 fragments that facilitate binding of C3-coated candidal cells. As a consequence, C3 fragments bound to the candidal surface are potential adhesins. Understanding the role of the complement system as adhesins that influence the course of a C. albicans infection is complicated by the presence of CR2 and CR3 like receptors on the yeast surface. The relative contributions to adhesion and tissue targeting by C3 fragments bound to these receptors and C3 fragments covalently linked via the activated thioester of C3b are not known. The C. albicans surface is dependent upon the conditions under which the cells are grown. The underlying hypothesis for this study is that variability in the candidal surface will influence the manner by which blastoconidia and hyphae initiate and regulate complement activation as well as the manner by which C3 fragments are bound. This variability in activation and binding of C3 fragments may greatly impact the function of C3 as an adhesin. This hypothesis will be examined by pursuit of five specific aims: 1.) to determine the qualitative and quantitative effects of the candidal cell surface on complement activation by C. albicans; 2.) to determine the effects of chemical and enzymatic modification of the C. albicans surface on complement activation; 3.) to determine the effects of the candidal iC3b receptor on kinetics of activation and binding of C3; 4.) to determine the effects of coating C. albicans with C3b or iC3b on trafficking of C. albicans to tissues in vivo; and 5) to determine the effects of coating C. albicans with C3b or iC3b on in vitro assays of adhesion. The in vitro assays of adhesion will include binding to endothelial cells, binding to tissues in an ex vivo assay, and binding to host cells under conditions of physiologic shear. Successful pursuit of the goals of this project will contribute to our understanding of the mechanism for and biological relevance of an aspect of C. albicans infection that has received little study in the past. Moreover, integration of results from this study with results from other projects in the Candida Adherence Mycology Research Unit will contribute to a comprehensive understanding of adhesion and the factors that influence adhesion.